We have evaluated a number of compounds that influence the growth of lung cancer cells such as inhibitors of the autocrine growth factors, gastrin releasing peptide, insulin-like growth factor, and transferrin. This experience has allowed us to focus on signal transduction pathways that are central to regulating cancer cell growth and potentially amenable to clinical intervention. We have published data suggesting that 5-HETE, a product of 5-lipoxygenase activation, may be a key intermediary in cancer cell growth. We have shown that lung cancer cells frequently express the message for a number of archidonic acid metabolizing enzymes. We have demonstrated with an in vivo model that this anti-proliferative effect of blocking the lipoxygenase pathway is potentially mediated via an apoptotic mechanism. We now also have data suggesting that the same approach that we reported for lung cancer is equally relevant to breast cancer and prostate cancers. This is important mechanistic information could allow rapid translation into clinical prevention application In a related approach, while evaluating for the relative importance of various arachidonic acid metabolizing enzymes in aerodigestive carcinogenesis, we found that head and neck cancers consistently over-express the enzymes, cyclooxygenase. The importance of this enzyme is in its role in the progression of colon cancer, since chronic administration of cyclooxygenase inhibitors such as aspirin is associated with a major reduction in colon cancer rates. As with our efforts in delivering retinoids directly to the affected tissue, under a clinical trial agreement with Procter and Gamble, we are testing a locally active form of a cyclooxygenase inhibitor. In collaboration with investigators from NIDCR and NIDCD, we have started a trial that will evaluate the clinical utility of local drug delivery in individuals with evidence of a precursor lesion for oral cancer. Our working hypothesis is that local delivery technique will enhance drug levels in the tissues affected by the early cancer without incurring the serious morbidity or mortality of systemic drug delivery. Experimental data suggests that suppressing oral inflammation with the local delivery of a cyclooxygenase inhibitor will change the local environment arresting the evolution of the oral cancer. The randomized Phase IIB trial is completed. There was no objective difference in the side effects of the Cox inhibitor compared to the placebo. THe full analysis of the study is expected to be complete with manuscript submittted in the next couple of months. Two institutions helped to complete this study including MD Anderson and University of Colorado Cancer Centers.We have published extensively on the clinical utility of the biomarker hnRNP A2/B1 to function in the early detection of lung cancer. It was suggested by the last Site Visit review, that we evolve to a more mechanistic orientation with our hnRNP A2/B1 studies. We therefore investigated the potential contribution of this molecule to the process of tumor carcinogenesis. Using a variety of model systems, our question is how hnRNP A2/B1 expression level affects lung cancer. Model systems that we have constructed alter the level of mRNA expression in either a mouse or human cell system. A range of potential target genes are modulated and we will describe the validation of the involvement of such pathways and their implications to carcinogenesis. ?